1. Field of the Invention
The present invention relates to a multifunctional aqueous ophthalmic preparation that is designed to be used topically in the eyes of humans and domestic animals. The present invention further relates to the provision of an aqueous solution of physiological pH, having hyperosmolality with respect to corneal stroma of the colloidal components only, which is useful for dehydrating edematous cornea even in the presence of damaged corneal epithelium when the barrier properties to small molecular weight electrolytes of the epithelial layer is lost. The invention also relates to an ophthalmic agent that is beneficial in promoting the permanent healing of epithelial defects. Still further, the invention relates to a solution that is capable of protecting the corneal epithelium from injury such as abrasion that may result from close and prolonged contact with solid surfaces, such as in the diagnostic procedures of tonography and tonometry, or any other procedure where a foreign solid object is brought in close contact with the preocular surface. Furthermore, the invention relates to an ophthalmic solution that can be used for irrigating purposes during prolonged intraocular surgical operations, e.g. vitrectomy, to preserve corneal thickness and clarity and to protect the cellular interfaces so that the incidence and the severity of postoperative complications involving the corneal epithelium or endothelium can be prevented. The invention also relates to the attainment of all the foregoing with significant decrease of ocular discomfort if present, and without optical interference with visual acuity. The invention further relates to an ophthalmic solution that can be formulated to have bactericidal activity without detectable decrease in its therapeutic efficacy.
2. Description of the Prior Art
The most powerful refractive medium of the eye, the cornea has to be transparent and must have an optically smooth surface to fulfill its function, the formation of a sharp visual image on the retina. The cornea is a normally transparent, mostly acellular connective tissue consisting of collagen fibers and mucopolysaccharides. This tissue is called the stroma, which is covered by several layers of epithelial cells on the exterior surface, while its interior surface is covered with a single layer of endothelial cells. The macromolecules of the stroma form a loosely connected matrix that contains about 80% by weight of aqueous fluid. This interstitial fluid of the stroma is nearly isotonic. The tissue, however, behaves as if it were somewhat dehydrated, since it tends to imbibe, i.e. absorb, additional fluid when immersed in physiological saline. This occurs because the additional osmolality of its macromolecular matrix causes a net flow of water into the stroma by osmosis, with the epithelium acting as a semipermeable membrane. Osmolality is a property of a solution which depends on the concentration of the solute molecules per unit weight of solvent and determines the amount of solvent absorbed by a particular substrate, usually in the presence of a semipermeable membrane. This tendency of water absorption is measured in terms of the so-called "imbibition pressure", which is about 40-60 torrs for the normal cornea. As the degree of hydration of the stroma increases, the imbibition pressure diminishes. Active transport of electrolytes and thus water out of the stroma by its boundary layers of cells keeps the stromal hydration at its normal, i.e. somewhat dehydrated, level in order to maintain its transparency. As the cornea imbibes water, it becomes progressively more cloudy diminishing visual acuity. A highly edematous cornea scatters so much light that it appears to be quite opaque.
The superficial epithelium can also become edematous. In such a case, droplets of fluid accumulate in the dilated intercellular spaces of the epithelium. Edematous epithelial tissue can loose its integrity; the cellular adhesiveness is lowered to such a degree that it can easily be abraded.
Corneal edema can result from various causes. A malfunction of the corneal endothelium usually results in severe corneal edema. Traumatized corneal epithelium, recurrent epithelial erosion, and epithelial discontinuities of other types can also result in corneal edema drastically reducing visual acuity.
Heretofore, corneal edema of sufficient severity to result in blurred vision has been treated with hypertonic salt solutions i.e. solutions which cause water to flow out of the cornea by having a higher tonicity than the solution within the cornea. Aqueous solutions of sodium chloride at concentrations of 2% and 5% by weight, instilled several times a day may provide symptomatic relief and thus temporarily restore visual acuity. Hydrogel lenses have also been used in conjunctin with hypertonic salt solutions and have been able to prolong the dehydrating effect of the hypertonic salt solution somewhat.
In addition to hypertonic sodium chloride solutions, hyperosmotic ointments containing 40% glucose are also employed in clinical practice, but its dehydrating effect is only slightly higher than that of the 5% sodium chloride solution. Hyperosmotic compositions are those containing a higher concentration of osmotically active components than that contained within a physiological salt solution containing 0.9% by weight of sodium chloride. Anhydrous glycerol is a highly effective dehydrating agent, but it is poorly tolerated by the eye of most patients as indicated by considerable discomfort, conjunctival injection, and photophobia, i.e. an abnormal visual intolerance of light.
All the foregoing hyperosmotic preparations have one weakness in common. They only have the desired dehydrating effect on the cornea, if the epithelium, which acts as an imperfect semipermeable membrane, is intact, since osmotic effects can occur only across a membrane that excludes at least one of the solutes. Hence, in many patients having corneal edema which is associated with epithelium of poor integrity, i.e. having epithelial discontinuities, the symptomatic treatment with hypertonic salt solutions or glucose ointment is ineffective, and may even be harmful, as the solute can readily penetrate the stroma achieving hypertonic levels inside the tissue which causes further imbibition of water with the resulting clouding of the cornea which diminishes visual acuity. Even in the presence of intact epithelium, the effect of hypertonic salt solutions is short-lived, as the drops are diluted and the excess salt is washed out of the eye by reflex tearing.
Some attempts have been made to improve the observed poor performance of hypertonic salt solutions especially in cases of corneal edema concurrent with epithelial discontinuity. Artificial tears containing "mucomimetic" polymers, i.e. polymers which mimic the action of naturally-occurring mucin which acts as a wetting agent in the eye and thus is responsible for tear film stability, have been used as ophthalmic vehicles for sodium chloride at hypertonic levels. However, in these polymeric solutions the osmolality of the dissolved polymers is negligibly small, and thus these attempts have added little to the performance of the hypertonic solutions other than lessening the discomfort upon application.
It is accordingly an object of the present invention to include colloidal components in the ophthalmic formulations at sufficiently high concentration so that their osmotic pressure is equivalent to or supercedes the imbibition pressure of a deturgescent cornea. The colloidal components have to be of such molecular size and shape that they cannot penetrate readily even the denuded stroma. The colloidal substance used also has to be sufficiently water-soluble and of low viscosity so that the required high solution concentration can be achieved before the limit of solubility is reached and without the high concentrations resulting in impractically high viscosity. A further object of the present invention is the provision of such solution with colloidal hyperosmolality where the hydrophilic polymers included readily adsorb at the cellular and tissue interfaces thereby prolonging the beneficial osmotic effect. It is also an object of this invention that the polymer layer adsorbed at the bio-interfaces should exert a beneficial effect on the healing of epithelium, on the adhesion of regenerating epithelium to the stroma and provide protection for the corneal epithelium against mechanical abrasion and other trauma besides prolonging the dehydrating osmotic effect for edematous corneas.